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The monomeric ferricytochrome c' from Rhodopseudomonas palustris strain 37 has been examined by 1H NMR spectroscopy at 45 degrees C and 360 MHz and at 55 degrees C and 200 MHz in 2H2O. The pH-dependent characteristics of the spectra have been analyzed in terms of two pK values at approximately 6 and approximately 8, the latter of which appears to correspond to the previously observed transition between an acidic species and a neutral species for this class of proteins. Previously determined rate constants (J. T. Jackson, G. N. La Mar, R. G. Bartsch, and M. A. Cusanovich, manuscript in preparation) permit, for the first time, connection between the downfield hyperfine shifted resonances of the two forms by spectral simulation. Contrary to previous suggestions (Emptage, M. H., Xavier, A. V., Wood, J.M., Alsaadi, B. M., Moore, G. R., Pitt, R. C., Williams, R. J. P., Ambler, R. P., and Bartsch, R. G. (1981) Biochemistry 20, 58-64; La Mar, G. N., Jackson, J. T., and Bartsch, R., (1981) J. Am. Chem. Soc. 103, 4405-4410), the data indicate that no additional ligand is involved in the transition but that the bonding between the iron and the axial histidyl ligand is severely altered. It is shown that this is consistent with extensive imidazolate character for the axial ligand in the neutral form.
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In wild-type bacteriorhodopsin light-induced proton release occurs before uptake at neutral pH. In contrast, in mutants in which R82 is replaced by a neutral residue (as in R82A and R82Q), only a small fraction of the protons is released before proton uptake at neutral pH; the major fraction is released after uptake. In R82Q the relative amounts of the two types of proton release, "early" (preceding proton uptake) and "late" (following proton uptake), are pH dependent. The main conclusions are that 1) R82 is not the normal light-driven proton release group; early proton release can be observed in the R82Q mutant at higher pH values, suggesting that the proton release group has not been eliminated. 2) R82 affects the pKa of the proton release group both in the unphotolyzed state of the pigment and during the photocycle. In the wild type (in 150 mM salt) the pKa of this group decreases from approximately 9.5 in the unphotolyzed pigment to approximately 5.8 in the M intermediate, leading to early proton release at neutral pH. In the R82 mutants the respective values of pKa of the proton release group in the unphotolyzed pigment and in M are approximately 8 and 7.5 in R82Q (in 1 M salt) and approximately 8 and 6.5 in R82K (in 150 mM KCl). Thus in R82Q the pKa of the proton release group does not decrease enough in the photocycle to allow early proton release from this group at neutral pH. 3) Early proton release in R82Q can be detected as a photocurrent signal that is kinetically distinct from those photocurrents that are due to proton movements from the Schiff base to D85 during M formation and from D96 to the Schiff base during the M-->N transition. 4) In R82Q, at neutral pH, proton uptake from the medium occurs during the formation of O. The proton is released during the O-->bacteriorhodopsin transition, probably from D85 because the normal proton release group cannot deprotonate at this pH. 5) The time constant of early proton release is increased from 85 microseconds in the wild type to 1 ms in R82Q (in 150 mM salt). This can be directly attributed to the increase in the pKa of the proton release group and also explains the uncoupling of proton release from M formation. 6) In the E204Q mutant only late proton release is observed at both neutral and alkaline pH, consistent with the idea that E204 is the proton release group. The proton release is concurrent with the O-->bacteriorhodopsin transition, as in R82Q at neutral pH.
The surface of a protein, or a membrane, is spotted with a multitude of proton-binding sites, some of which are only a few angstroms apart. When a proton is released from one site, it propagates through the water by a random walk under the bias of the local electrostatic potential determined by the distribution of the charges on the protein. Some of the released protons disperse into the bulk, but during the first few nanoseconds, the released protons can be trapped by encounter with nearby acceptor sites. This process resembles a scenario which corresponds with the time-dependent Debye-Smoluchowski equation. In the present study, we investigated the mechanism of proton transfer between sites that are only a few angstroms apart, using as a model the proton exchange between sites on a small molecule, fluorescein, having two, spectrally distinguishable, proton-binding sites. The first site is the oxyanion on the chromophore ring structure. The second site is the carboxylate moiety on the benzene ring of the molecule. Through our experiments, we were able to reconstruct the state of protonation at each site and the velocity of proton transfer between them. The fluorescein was protonated by a few nanosecond long proton pulse under specific conditions that ensured that the dye molecules would be protonated only by a single proton. The dynamics of the protonation of the chromophore were measured under varying initial conditions (temperature, ionic strength, and different solvents (H(2)O or D(2)O)), and the velocity of the proton transfer between the two sites was extracted from the overall global analysis of the signals. The dynamics of the proton transfer between the two proton-binding sites of the fluorescein indicated that the efficiency of the site-to-site proton transfer is very sensitive to the presence of the screening electrolyte and has a very high kinetic isotope effect (KIE = 55). These two parameters clearly distinguish the mechanism from proton diffusion in bulk water. The activation energy of the reaction (E(a) = 11 kcal mol(-1)) is also significantly higher than the activation energy for proton dissociation in bulk water (E(a) approximately 2.5 kcal mol(-1)). These observations are discussed with respect to the effect of the solute on the water molecules located within the solvation layer.
Evidence has been gathering from several laboratories that protons in proton-pumping membranes move along or within the bilayer rather than exchange with the bulk phase. These experiments are typically conducted on the natural membrane in vivo or in vitro or on fragments of natural membrane. Anionic lipids are present in all proton-pumping membranes. Model studies on the protonation state of the fatty acids of liposomes containing entrapped water show that the bilayers always contain mixtures of protonated and deprotonated carboxylates. Protonated fatty acids form stable acid-anion pairs with deprotonated fatty acids through unusually strong hydrogen bonds. Such acid-anion dimers have a single negative charge, which is shared by the four negative oxygens of both headgroups. The two pK values of the resulting dimer will be significantly different from the pK of the monomeric species, so that the dimer will be stable over a wide pH range. It is proposed that anionic lipid headgroups in biological membranes share protons as acid-anion dimers and that anionic lipids thus trap and conduct protons along the headgroup domain of bilayers that contain such anionic lipids. Protons pumped from the other side of the membrane may enter and move within the headgroup sheet because the protonation rate of negatively charged proton acceptors is 5 orders of magnitude faster than that of water. Protons trapped in the acidic headgroup sheet need not leave this region in order to be utilized by a responsive proton-translocating pore (a transport protein using the proton gradient). Experiments suggest the proton concentration in the headgroup domain may vary widely and the anionic lipid headgroup sheet may therefore function as a proton buffer. Due to the Gouy-Chapman-Stern layer at polyanionic surfaces, anionic lipids will also sequester protons from the bulk solution at low and moderate ionic strengths. At high ionic strength metal cations may replace protons sequestered near the headgroups, but these cations cannot substitute for protons in the "proton-conducting pathway," which is based on hydrogen bonding.
A number of calculated structures of heterogeneous proton-bound dimers containing monomers such as acetonitrile, cyanamide, vinylene carbonate, and propiolactone, which have high dipole moments, are presented. These proton-bound dimers are predicted to have a structural anomaly pertaining to the bond distances between the central proton and the basic sites on each of the monomers. The monomers with the high dipole moments also have the larger proton affinity and, on the basis of difference in proton affinities, it would be expected that the proton would be closer to this monomer than the one with the lower proton affinity. However, the proton is found to lie substantially closer to the monomer with the lower proton affinity in most cases, unless the difference in proton affinity is too large. Simply stated, the difference in proton affinities is smaller than the difference in the affinity to form an ion-dipole complex for the two monomers and it is the larger affinity for the high dipole moment monomer (which also has the higher proton affinity) to form an ion-dipole complex that is responsible for the proton lying closer to the low proton affinity monomer. The bond distances between the central proton and the monomers are found to be related to the difference in proton affinity. It is found, though, that the proton-bound dimers can be grouped into two separate groups, one where the proton-bound dimer contains a high dipole moment monomer and one group where the proton-bound dimer does not contain a high dipole moment monomer. From these plots it has been determined that a high dipole moment monomer is one that has a dipole moment greater than 2.9 D.
The bacterial reaction center (RC) converts light into chemical energy through the reduction of an internal quinone molecule Q(B) to Q(B)H(2). In the native RC, proton transfer is coupled to electron transfer and is not rate-controlling. Consequently, proton transfer is not directly observable, and its rate was unknown. In this work, we present a method for making proton transfer rate-controlling, which enabled us to determine its rate. The imidazole groups of the His-H126 and His-H128 proton donors, located at the entrance of the transfer pathways, were removed by site-directed mutagenesis (His --> Ala). This resulted in a reduction in the observed proton-coupled electron transfer rate [(Q(A)(-)(*)Q(B))Glu(-) + H(+) --> (Q(A)Q(B)(-)(*))GluH], which became rate-controlled by proton uptake to Glu-L212 [Adelroth, P., et al. (2001) Biochemistry 40, 14538-14546]. The proton uptake rate was enhanced (rescued) in a controlled fashion by the addition of imidazole or other amine-containing acids. From the dependence of the observed rate on acid concentration, an apparent second-order rate constant k((2)) for the "rescue" of the rate was determined. k((2)) is a function of the proton transfer rate and the binding of the acid. The dependence of k((2)) on the acid pK(a) (i.e., the proton driving force) was measured over 9 pK(a) units, resulting in a Brönsted plot that was characteristic of general acid catalysis. The results were fitted to a model that includes the binding (facilitated by electrostatic attraction) of the cationic acid to the RC surface, proton transfer to an intermediate proton acceptor group, and subsequent proton transfer to Glu-L212. A proton transfer rate constant of approximately 10(5) s(-)(1) was determined for transfer from the bound imidazole group to Glu-L212 (over a distance of approximately 20 A). The same method was used to determine a proton transfer rate constant of 2 x 10(4) s(-)(1) for transfer to Q(B)(-)(*). The relatively fast proton transfer rates are explained by the presence of an intermediate acceptor group that breaks the process into sequential proton transfer steps over shorter distances. This study illustrates an approach that could be generally applied to obtain information about the individual rates and energies for proton transfer processes, as well as the pK(a)s of transfer components, in a variety of proton translocating systems.
Despite much experimental and computational study, key aspects of the mechanism of reduction of dihydrofolate (DHF) by dihydrofolate reductase (DHFR) remain unresolved, while the secondary DHFR-catalyzed reduction of folate has been little studied. Major differences between proposed DHF mechanisms are whether the carboxylate group of the conserved active-site Asp or Glu residue is protonated or ionized during the reaction, and whether there is direct protonation of N5 or a proton shuttle from an initially protonated carboxylate group via O4. We have addressed these questions for both reduction steps with a comprehensive set of ab initio quantum chemical calculations on active-site fragment complexes, including the carboxyl side chain and, progressively, all other polar active-site residue groups including conserved water molecules. Addition of two protons in two steps was considered. The polarization effects of the remainder of the enzyme system were approximated by a dielectric continuum self-consistent reaction field (SCRF) model using an effective dielectric constant (epsilon) of 2. Optimized geometries were calculated using the density functional (B3LYP) method and Onsager SCRF model with the 6-31G basis. Single-point energy calculations were then carried out at the B3LYP/6-311+G level with either the Onsager or dielectric polarizable continuum model. Additional checking calculations at MP2 and HF levels, or with other basis sets or values of epsilon, were also done. From the results, the conserved water molecule, corresponding to W206 in the E. coli DHFR complexes, that is H-bonded to both the OD2 oxygen atom of the carboxyl (Asp) side chain and O4 of the pterin/dihydropterin ring, appears critically important and may determine the protonation site for the enzyme-bound substrates. In the absence of W206, the most stable monoprotonated species are the neutral-pair 4-enol forms of substrates with the carboxyl group OD2 oxygen protonated and H-bonded to N3. If W206 is included, then the most stable forms are still the neutral-pair complexes but now for the N3-H keto forms with the protonated OD2 atom H-bonding with W206. A second proton addition to these complexes gives protonations at N8 (folate) or N5 (DHF). Calculated H-bond distances correlate well with those for the conserved W206 observed in many X-ray structures. For all structures with occluded M20 loop conformations (closed active site), OD2-N3 distances are less than OD2-NA2 distances, which is consistent with those calculated for protonated OD2 complexes. Thus, the results (B3LYP; epsilon = 2 calculations) support a mechanism for both folate and DHF reduction in which the OD2 carboxyl oxygen is first protonated, followed by a direct protonation at N8 (folate) and N5 (DHF) to obtain the active cation complexes, i.e., doubly protonated. The results do not support a proposed protonated carboxyl with DHF in the enol form for the Michaelis complex, nor an ionized carboxyl with protonated enol-DHF as a catalytic intermediate. However, as additional calculations for the monoprotonated complete complexes show a reduction in the energy differences between the neutral-pair keto and ion-pair keto (N8- or N5-protonated) forms, we are extending the treatment using combined quantum mechanics and molecular mechanics (QM/MM) and molecular dynamics simulation methods to refine the description of the protein/solvent environment and prediction of the relative stabilization free energies of the various (OD2, O4, N5, and N8) protonation sites.
Hydrogen bond networks, consisting of hydrogen bonded waters anchored by polar/acidic amino acid sidechains, are often present in the vicinity of the oxygen binding clefts of P450s. Density functional and quantum dynamics calculations of a O(2) binding cleft network model of cytochrome P450eryF(CYP107A1) indicate that such structural motifs facilitate ultrafast proton transfer from network waters to the dioxygen of the reduced oxyferrous species via a multiple proton translocation mechanism with barriers of 7-10 kcal/mol on its doublet ground state, and that the energies of the proton transfer reactant and constrained proton transfer products have an electronic and oxidation state dependence [J. Am. Chem. Soc. 124 (2002) 1430]. In the present study, the origin of the oxidation state dependence is shown to have its roots in differential proton affinities while the electronic state dependence of the reduced oxyferrous heme has its origins in subtle differences in network topologies near the transition state of the initial proton transfer event. Relaxed potential surface scans and unconstrained proton transfer product optimizations indicate that the proton transfer product in both the singlet oxyferrous heme and the reduced oxyferrous heme species in a quartet state are not viable stable (bound) states relative to the reactant form. While the proton affinity of H(3)O(+) is sufficient for it to protonate both the oxyferrous and the reduced oxyferrous heme species, hydrogen bond network stabilized water is only capable of protonating the reduced oxyferrous form. This interpretation is substantiated by study of the NO bound reduced ferrous heme of P450nor, which is isoelectronic with the oxyferrous heme and has a similar proton affinity. Density functional calculations on a more extensive O(2) binding cleft model support the multiple proton translocation mechanism of transfer but indicates that the significant negative charge density on the bound dioxygen of the reduced oxyferrous heme species, in its doublet ground state, polarizes the associated hydrogen bond network sufficiently so as to result in short, strong, low-barrier hydrogen bonds. The computed O-H-O bond distances are less than 2.55 A and have a near degeneracy of the proton transfer reactant and initial (sudden) proton transfer products. These low-barrier hydrogen bond features, in addition to the finding of a (zero point uncorrected) barrier of 1.3 kcal/mol, indicate that proton transfer from water to the distal oxygen should be rapid, facile and may not require large curvature tunneling as originally suggested by use of a smaller model. An initial assessment of protonation of the reduced oxyferrous heme distal oxygen by a model of 6-deoxyerythronolide B (6-DEB) indicates it to be low barrier (3.8 kcal/mol) and exothermic (-2.9 kcal/mol). The combined results indicate the plausibility of simultaneous diprotonation of the distal oxygen of the reduced oxyferrous heme, leading to O-O bond scission, using the combined water network and 6-DEB substrate protonation agents.
In spite of many still unsolved problems, the mechanism and energetics of the light-driven proton transport are now basically understood. Energy captured during photoexcitation, and retained in the form of bond rotations and strains of the retinal, is transformed into directed changes in the pKa values of vectorially arranged proton transfer groups. The framework for the spatial and temporal organization of these changes is provided by the protein near the retinal Schiff base. The transport is completed by proton transfer among three essential groups in three domains lying roughly parallel with the membrane plane (Fig. 1): (a) the anionic D85 that is included in a complex of residues on the extracellular side containing also R82, D212, Y57 and bound water; (b) the protonated Schiff base; and (c) the protonated D96 that is included in a complex of residues on the cytoplasmic side containing also R227, T46, S226, and bound water. Other neighboring polar groups and water bound elsewhere which play a role in the transport do so either by further influencing the pKa values of the three protonable groups, or by providing passive pathways for proton transfer. The Schiff base proton, destabilized after photoexcitation, is transferred to the low pKa group D85 located on the extracellular side. The access of the deprotonated Schiff base then changes to the cytoplasmic side (the 'reprotonation switch') and its proton affinity increases. Finally, the proton of the high pKa group D96, with access to the cytoplasmic side, is destabilized by a protein conformational change through rearrangement of R227, T46, S226 and bound water, and becomes transferred to the Schiff base. As shown schematically in Fig. 3, these internal events are coupled to proton release and uptake at the two aqueous surfaces. The charge of the extracellular hydrogen-bonded complex is redistributed upon protonation of D85, and if the pH is above the pKa of the complex a proton is released to the bulk. After reprotonation of the Schiff base the pKa of the cytoplasmic hydrogen-bonded complex is raised well above the pH, and D96 regains a proton from the bulk. If the pH is lower than the pKa of the extracellular complex the proton release is delayed until the end of the photocycle. In either sequence there is net transfer of a proton from the cytoplasmic to the extracellular phase. The transfer of excess free energy from the chromophore to the protein, and finally to the transported proton, is described by a characteristic thermodynamic cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
In this paper we present calculations for the design of a particle selection system for laser-accelerated proton therapy. Laser-accelerated protons coming from a thin high-density foil have broad energy and angular spectra leading to dose distributions that cannot be directly used for therapeutic applications. Our solution to this problem is a compact particle selection and collimation device that delivers small pencil beams of protons with desired energy spectra. We propose a spectrometer-like particle selection and beam modulation system in which the magnetic field will be used to spread the protons spatially according to their energies and emitting angles. Subsequently, an aperture will be used to select the protons within a therapeutic window of energy (energy modulation). It will be shown that for the effective proton spatial differentiation, the primary collimation device should be used, which will collimate protons to the desired angular distribution and limit the spatial mixing of different energy protons once they have traveled through the magnetic system. Due to the angular proton distribution, the spatial mixing of protons of different energies will always be present and it will result in a proton energy spread with the width depending on the energy. For 250 MeV protons, the width (from the maximum to the minimum energy) is found to be 50 MeV for the magnetic field configuration used in our calculations. As the proton energy decreases, its energy width decreases as well, and for 80 MeV protons it equals 9 MeV. The presence of the energy width in the proton energy distribution will modify the depth dose curves needed for the energy modulation calculation. The matching magnetic field setup will ensure the refocusing of the selected protons and the final beam will be collimated by the secondary collimator. The calculations presented in this article show that the dose rate that the selection system can yield is on the order of D=260 Gy/min for a field size of 1 x 1 cm2.
The catalytic strategies of enzymes (such as citrate synthase) whose reactions require the abstraction of the alpha-proton of a carbon acid remain elusive. Citrate synthase readily catalyzes solvent proton exchange of the methyl protons of dethiaacetyl-coenzyme A, a sulfur-less, ketone analog of acetyl-coenzyme A, in its ternary complex with oxaloacetate. Because no further reaction occurs with this analog, it provides a uniquely simple probe of the roles of active site interactions on carbon acid proton transfer catalysis. In view of the high reactivity of the analog for proton transfer to the active site base, its failure to further condense with oxaloacetate to form a sulfur-less analog of citryl-coenzyme A was unexpected, although we offer several possible explanations. We have measured the rate constants for exchange, k(exch), at saturating concentrations of the analog for six citrate synthase mutants with single changes in active site residues. Comparisons between the values of k(exch) are straightforward in two limits. If the rate of exchange of the transferred proton with solvent protons is rapid, then k(exch) equals the forward rate constant for proton transfer, and k(exch) values for different mutants compare directly the rate constants for proton transfer. If the exchange of the transferred proton with protons in the bulk solution is the slow step and the equilibrium constant for proton transfer is unfavorable (as is likely), then k(exch) equals the product of the equilibrium constant for proton transfer and the rate constant for exchange of the transferred proton with bulk solvent. If that exchange rate with bulk solution remains constant for a series of mutant enzymes, then k(exch) values compare the equilibrium constants for proton transfer. The importance of the acetyl-CoA site residues, H274 and D375, is confirmed with D375 again implicated as the active site base. The results with the series of oxaloacetate site mutants, H320X, strongly suggest that activation of the first substrate, oxaloacetate, through carbonyl bond polarization, not just oxaloacetate binding in the active site, is required for the enzyme to efficiently catalyze proton transfer from the methyl group of the second substrate.
In mitochondria, ATP synthesis is coupled to oxygen consumption by the proton electrochemical gradient established across the mitochondrial inner membrane in a process termed oxidative phosphorylation. It has long been known from stoichiometric studies that ATP synthesis is not perfectly coupled to oxygen consumption. The major inefficiency in the system is leakage of protons across the mitochondrial inner membrane driven by the proton electrochemical gradient. The kinetics of the proton leak can be determined indirectly, by measuring the oxygen consumption of mitochondria under non-phosphorylating conditions (plus oligomycin) as a function of the proton electrochemical gradient. This experimental system provides a convenient means to investigate inner membrane permeability to protons and the effect of factors that may effect that permeability. In this paper we review some results from our laboratory of indirect measurement of mitochondrial proton leak and how it has been applied to investigate the effect of aging, obesity and thyroid status on proton leak. The results show that (i) proton leak in isolated liver mitochondria is not significantly different in a comparison of young and old rats, in contrast (ii) there is an apparent increase in proton leak in in situ mitochondria in hepatocytes from old rats when compared to those from young rats, (iii) proton leak in neuronal mitochondria in situ in synaptosomes is not significantly different in young and old rats, (iv) proton leak is greater in isolated liver mitochondria from ob/ob mice compared to lean controls, (v) acute leptin (OB protein) administration restores the increased leak rate in isolated liver mitochondria from ob/ob mice to that of lean controls, (vi) administration of thyroid hormone (T3) increases proton leak in rat muscle mitochondria, and (vii) proton leak in muscle mitochondria is insensitive to the presence of GDP. It is proposed that the experimental system described here for measuring proton leak, is an ideal functional assay for determining whether the novel uncoupling proteins increase inner membrane permeability to protons.
PURPOSE: A comparative treatment planning study was undertaken between proton and photon therapy in uveal melanoma to assess the potential benefits and limitations of these treatment modalities. A fixed proton horizontal beam (OPTIS) and intensity-modulated spot-scanning proton therapy (IMPT), with multiple noncoplanar beam arrangements, was compared with linear accelerator-based stereotactic radiotherapy (SRT), using a static and a dynamic micromultileaf collimator and intensity-modulated RT (IMRS). METHOD AND MATERIALS: A planning CT scan was performed on a brain metastasis patient, with a 3-mm acquisition slice spacing and the patient looking at a luminous spot with the eyes in three different positions (neutral and 25 degrees right and left). Four different gross tumor volumes were defined for each treatment technique. These target scenarios represented different locations (involving vs. not involving the macula and temporal vs. nasal) and volumes (10 x 6 mm vs. 16 x 10 mm) to challenge the proton and photon treatment techniques. The planning target volume was defined as the gross tumor volume plus 2 mm laterally and 3 mm craniocaudally for both modalities. A dose homogeneity of 95-99% of the planning target volume was used as the "goal" for all techniques. The dose constraint (maximum) for the organs at risk (OARs) for both the proton and the SRT photon plans was 27.5, 22.5, 20, and 9 CGE-Gy for the optic apparatus, retina, lacrimal gland, and lens, respectively. The dose to the planning target volume was 50 CGE-Gy in 10 CGE-Gy daily fractions. The plans for proton and photon therapy were computed using the Paul Scherrer Institute and BrainSCAN, version 5.2 (BrainLAB, Heimstetten, Germany) treatment planning systems, respectively. Tumor and OARs dose-volume histograms were calculated. The results were analyzed using the dose-volume histogram parameters, conformity index (CI(95%)), and inhomogeneity coefficient. RESULTS: Target coverage of all simulated uveal melanomas was equally conformal with the photon and proton modalities. The median CI(95%) value was 1.74, 1.86, and 1.83 for the static, dynamic, and IMSRT plans, respectively. With proton planning, the median CI(95%) was 1.88 for OPTIS and substantially improved with IMPT in some tumor cases (median CI(95%), 1.29). The tumor dose homogeneity in the proton plans was, however, always better than with SRT photon planning (median inhomogeneity coefficient 0.1 and 0.15 vs. 0.46, 0.41, and 0.23 for the OPTIS and IMPT vs. the static, dynamic, and IMSRT plans, respectively). Compared with the photon plans, the use of protons did not lead to a substantial reduction in the homolateral OAR total integral dose in the low- to high-dose level, except for the lacrimal gland. The median maximal dose and dose at the 10% volume with the static, dynamic, and IMSRT plans was 33-30.8, 31.8-28, and 35.8-49 Gy, respectively, for the lacrimal gland, a critical organ. For protons, only the OPTIS plans were better, with a median maximal dose and dose at the 10% volume using OPTIS and IMPT of 19.2 and 8.8 and 25.6 and 23.6 CGE, respectively. The contralateral OARs were completely spared with the proton plans, but the median dose delivered to these structures was 1.2 Gy (range, 0-6.3 Gy) with the SRT photon plans. CONCLUSION: These results suggest that the use of SRT photon techniques, compared with protons, can result in similar levels of dose conformation. IMPT did not increase the degree of conformality for this small tumor. Tumor dose inhomogeneity was, however, always increased with photon planning. Except for the lacrimal gland, the use of protons, with or without intensity modulation, did not increase homolateral OAR dose sparing. The dose to all the contralateral OARs was, however, completely eliminated with proton planning.
This review briefly traces the historical developments of proton radiobiology, radiosurgery and radiotherapy for the benefit of young researchers and clinicians entering into this field. In preparing to use protons in radiosurgery and radiotherapy, radiobiological effects of protons were studied extensively by various groups, including the University of California at Berkeley, the University of Uppsala, Massachusetts General Hospital, and the Harvard Cyclotron Laboratory. Considerable work on proton radiobiology was also done because protons are a major component of the radiation environment in space. The biological effects of proton beams were found to be quantitatively and qualitatively similar to conventional radiations used in radiotherapy. The relative biological effectiveness (RBE) of protons suitable for large-field radiotherapy, compared with 60Co gamma-rays, is generally in the range 1.0-1.25, and remains the same with depth of penetration, except for the descending portion of the depth-dose curve. Also, unlike other heavier charged particles and neutrons, the RBE of high-energy protons, which are suitable for large-field radiotherapy, compared with 60Co gamma-rays, is generally found to be independent of the fraction size in in vivo experiments. The oxygen enhancement ratio for high-energy protons is not significantly different from that of X-rays. An RBE = 1.1, compared with 60Co gamma-rays, is generally used in the clinical application of protons; however, the radiobiological data on mouse, rat, rabbit and primate suggest that the gastrointestinal tissues may be relatively more sensitive to protons. About 13,000 patients have been treated with protons at about 15 facilities around the world. Nearly half of these patients were neurosurgical patients treated with stereotactic radiosurgery. The pioneering efforts at the Harvard Cyclotron in collaboration with the Massachusetts General Hospital and the Massachusetts Eye and Ear Infirmary were responsible for the development of proton treatment for choroidal melanoma and for the tumours of the skull base and spine. There has been extensive confirmation of these results by other groups, especially the groups at Lawrence Berkeley Laboratory and Paul Scherrer Institute. The first medically dedicated proton facility is in operation at Loma Linda University in California. The construction in the USA of another proton treatment facility at Massachusetts General Hospital has been decided upon, and there are plans for many more worldwide.
Clinical results from various trials have demonstrated the viability of protons in radiation therapy and radiosurgery. This has motivated a few large medical centers to design and build expensive hospital based proton facilities based proton facilities (current cost estimates for a proton facility is around 100 million US dollars). Until this development proton therapy was done using retrofitted equipment originally designed for nuclear experiments. There are presently only three active proton therapy centers in the United States, 22 worldwide. However, more centers are under construction and being proposed in the US and abroad. The important difference between proton and x-ray therapy is in the dose distribution. X-rays deposit most of their dose at shallow depths of a few centimeters with a gradual decay with depth in the patient. Protons deliver most of their dose in the Bragg peak, which can be delivered at most clinically required depths followed by a sharp fall-off. This sharp falloff makes protons sensitive to variations in treatment depths within patients. Treatment planning incorporates all the knowledge of protons into a process, which allows patients to be treated accurately and reliably. This process includes patient immobilization, imaging, targeting, and modeling of planned dose distributions. Although the principles are similar to x-ray therapy some significant differences exist in the planning process, which described in this paper. Target dose conformality has recently taken on much momentum with the advent of intensity modulated radiation therapy (IMRT) with photon beams. Proton treatments provide a viable alternative to IMRT because they are inherently conformal avoiding normal tissue while irradiating the intended targets. Proton therapy will soon bring conformality to a new high with the development of intensity modulated proton therapy (IMPT). Future challenges include keeping the cost down, increasing access to conventional proton therapy as well as the clinical implementation of IMPT. Computing advances are making Monte Carlo techniques more accessible to treatment planning for all modalities including proton therapy. This technique will allow complex delivery configurations to be properly modeled in a clinical setting.